PROJECT SUMMARY/ABSTRACT ? MOLECULAR THERAPEUTICS PROGRAM The Molecular Therapeutics (MT) Program, led by El-Deiry and Golemis, is comprised of 35 Primary Members and 23 Collaborating Members. Program funding is $10.3M (project direct costs) annually, including $6.1M in peer-reviewed funding of which $2M is from the NCI. MT members have been highly productive and interactive during the past funding cycle, generating 911 publications, with 20% representing intra- programmatic and 18% representing inter-programmatic collaborations. The scientific mission of the MT Program is to improve cancer therapy by integrating investigation of essential signaling mechanisms of tumor cells with the design and application of new clinical trial strategies. To this end, the program is a highly collaborative translational program that brings together basic and clinical investigators focused on the themes of molecular structure and computation, signaling pathways and preclinical studies of targeted therapeutics, and early phase clinical trials with correlative science. The program has three overarching themes: 1) to develop and apply methods relevant to Structure and Computation to inform the mechanism of cancer-predisposing mutations, and to design protein-targeted therapies; 2) to integrate Cancer Signaling and Therapeutics, to identify therapeutically targetable vulnerabilities and therapeutic biomarkers through the use of candidate and screening approaches; and 3) to perform Early Phase Clinical Trials to translate program science to and from the clinic. The MT Program fosters intra-programmatic interactions through regular bi-weekly program meetings, program-wide retreats, and focused theme-group retreats. Inter- programmatic collaboration is promoted through retreats and Translational Research Disease Groups (TRDGs) that cut across programs and disciplines. The MT program also drives translational investigator- initiated clinical trials at FCCC through multidisciplinary intra- and inter-programmatic interactions and support from translational cores. MT Program members hold leadership positions within the National Comprehensive Cancer Network that sets clinical oncology practice guidelines. TRDGs bridge clinical and basic research activities, tumor boards, Clinical Trial Operations and the research programs to promote innovative, inter- programmatic Investigator-Initiated Trials (IITs), interdisciplinary collaborations, extramural funding, and educational goals. Since 2011, 18 IITs have opened at FCCC, with many incorporating genomic testing strategies to provide mechanistic insights into therapeutic response. Treatment-interventional trial accrual at FCCC rose from 358 in 2011 to 668 in 2014. The activities of the MT program are strongly supported by all 12 of the Shared Resources, with particular reliance on the Cell Culture Facility, High Throughput Screening Facility, Biostatistics and Bioinformatics Facility, Genomics Facility, Biosample Repository Facility, Histopathology Facility, and Laboratory Animal Facility.